Angiogenesis is a phenomenon wherein a new vascular network is formed from existing blood vessels and is observed mainly in fine blood vessel. Angiogenesis is originally a physiological phenomenon and is essential for blood vessel formation at a viviparous period, but it is usually observed only at a limited site such as endometrium or follicle or at a limited period such as a wound healing process in adults. However, pathologic angiogenesis is caused in diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoid choroidal angiopathy, diabetic macular degeneration, psoriasis vulgaris and pultaceous arteriosclerosis, and pathologic angiogenesis closely relates to the progress of pathema of these diseases. It is considered that angiogenesis is adjusted by balance between its promotive factor and inhibitory factor, and angiogenesis is caused by losing of the balance. (See Molecular Medicine vol. 35, special issue, “Molecular Mechanism of Symptom and Pathema”, Nakayama Shoten, 73-74 (1998) and Protein, Nucleic Acid, Enzyme, extra number, “The Most Advanced Development of New Drugs”, Kyoritsu Shuppan; 1182-1187 (2000).)
A vascular endothelial growth factor (hereinafter abbreviated as “VEGF”) is a factor which specifically acts on a receptor (Flt-1, KDR/Flk-1 or the like) existing on the surface of vascular endothelial cells, thereby promoting growth and migration of the vascular endothelial cells, construction of a capillary vessel network due to vasculogenesis. VEGF also augments vascular permeability, and plays an important role in occurrence of angiogenesis. Accordingly, there have been many reports on attempts to treat diseases in which angiogenesis and the augmentation of vascular permeability are involved by inhibiting VEGF to control the occurrence of angiogenesis and the augmentation of vascular permeability. Examples of drugs to be used for the treatment are 2-indolinone derivatives (WO 98/50356), phthalazine derivatives (WO 98/35958), quinazoline derivatives (WO 97/30035), anthranilic acid amide derivatives (WO 00/27819), 2-aminonicotinic acid derivatives (WO 01/55114) and the like. However, compounds which have 4-pyridylalkylthio group as a substituent aren't described in these patent documents at all.
On the other hand, Il Farmaco-Ed. Sc., 18, 288 (1963) and WO 02/066470 report compounds having chemical structures relatively close to those of the compounds having 4-pyridylalkylthio as a substituent. The compounds disclosed in Il Farmaco-Ed. Sc., 18, 288 (1963) are benzoic acid amide derivatives having 3-pyridylalkylthio, and antibacterial actions are recited as their use. WO 02/066470 relates to substituted alkylamine derivatives and their pharmaceutical use, and discloses compounds having enormous combinations of chemical structures. WO 02/066470 discloses a derivative having 4-pyridylalkylamino as one example among those compounds, but does not describe 4-pyridylalkylthio derivatives at all.